1. Field of the Invention
The invention relates to a process for preparing 6,6-dialkoxy-5-hydroxy-3-oxohexanoic acid esters of the general formula 
in which R1 and R2 are identical or different and are C1-6-alkyl.
2. Background Art
The abovementioned compounds are important synthesis building blocks for preparing numerous HMG-CoA reductase inhibitors (WO-A 92/10503).
According to WO-A 92/10503, these compounds are obtained by reacting an acetic acid ester with a xcex3-dialkoxy-xcex2-hydroxy ester. However, this synthesis has the disadvantage that the latter starting material is difficult to obtain and therefore expensive.
It was the object of the invention to develop a simpler and more cost-effective route to the abovementioned synthesis building blocks.
This object could be achieved by the process according to the invention.
According to the invention, this involves reacting an alkyl acetoacetate of the general formula 
in which R1 is as defined above in the presence of a base with an aldehyde of the formula 
in which R2 is as defined above.
A C1-6-alkyl group is hereinbelow understood as a linear or branched alkyl group with 1 to 6 carbon atoms, namely methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, pentyl and its isomers and hexyl and its isomers. Preference is given to the C1-4-alkyl groups mentioned by name.
The process according to the invention has the advantage that the acetoacetic esters of the general formula II are available industrially.
Acetoacetic esters of the general formula II are obtained by reacting diketenes with the appropriate alcohol. The acetoacetic ester of the formula II may also be provided in situ, starting from diketene. Preferred acetoacetic esters of the general formula II are the methyl ester, the ethyl ester, the n-propyl ester, the isopropyl ester, the n-butyl ester, the isobutyl ester and the tert-butyl ester, particularly preferably the tert-butyl ester.
The aldehydes of the general formula III are generally commercially available. The preferred aldehyde of the formula III is glyoxal 1,1-dimethyl acetal.
The process according to the invention is advantageously carried out in an organic solvent in the substantial absence of water. Suitable solvents are ethers, such as, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, etc., aromatic compounds, such as benzene or toluene, or hydrocarbons, such as hexane, and mixtures of the abovementioned solvents.
The reaction temperature is generally chosen in a range from xe2x88x9280xc2x0 C. to 130xc2x0 C., preferably in a range from xe2x88x9240xc2x0 C. to 20xc2x0 C.
A base is used with the aim of forming the dianion of the alkyl acetoacetate of the general formula II. In principle, this dianion formation can be carried out directly using a strong base, such as, butyllithium, methyllithium, phenyllithium or sodium amide, lithium diisopropylamide or lithium hexamethyldisilazane.
In general, a two-step process is employed, by initially deprotonating the xe2x80x94CH2xe2x80x94 function using a relatively weak and also cost-effective base, and carrying out the dianion formation only in the second step using the abovementioned strong base. Suitable relatively weak bases are metal hydrides, such as, alkali metal hydrides and alkaline earth metal hydrides, preferably sodium hydride, but also secondary amines (preferably pyrrolidine), which forms an enamine as anion equivalent with the acetoacetic ester. In the latter case, the dianion is understood as the anion of the corresponding enamine.
The desired 6,6-dialkoxy-5-hydroxy-3-oxohexanoic acid ester can be obtained in a manner familiar to the person skilled in the art, for example by neutralization of the reaction mixture and subsequent extraction with a suitable solvent.